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The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils
 
 
Article

Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment

1
Metabolic Physiopathology Research Group, Experimental Medicine Department, Lleida University-Lleida Biochemical Research Institute (UdL-IRBLleida), E25198 Lleida, Spain
2
Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L’Hospitalet de Llobregat, E08907 Barcelona, Spain
3
Department of Pathology and Experimental Therapeutics, University of Barcelona, E08900 Barcelona, Spain
4
CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Ministry of Economy and Competitiveness, E08900 Barcelona, Spain
5
Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, E08907 Barcelona, Spain
6
Senior Consultant, Bellvitge University Hospital, E08900 Barcelona, Spain
7
Institute of Neurosciences, University of Barcelona, E08000 Barcelona, Spain
8
Edifici Biomedicina I, Avda Rovira Roure, E25196 Lleida, Spain
*
Author to whom correspondence should be addressed.
Academic Editors: Yazi Ke and Adam K. Walker
Int. J. Mol. Sci. 2021, 22(16), 8853; https://doi.org/10.3390/ijms22168853
Received: 7 July 2021 / Revised: 12 August 2021 / Accepted: 13 August 2021 / Published: 17 August 2021
Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes. View Full-Text
Keywords: TDP-43; Jun; REST; ERK; mitochondria; cell stress; aggregation; transcription factors; transgenic mice; subcellular fractionation TDP-43; Jun; REST; ERK; mitochondria; cell stress; aggregation; transcription factors; transgenic mice; subcellular fractionation
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MDPI and ACS Style

Rossi, C.; Fernàndez, A.; Torres, P.; Ramirez-Nuñez, O.; Granado-Serrano, A.B.; Fontdevila, L.; Povedano, M.; Pamplona, R.; Ferrer, I.; Portero-Otin, M. Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment. Int. J. Mol. Sci. 2021, 22, 8853. https://doi.org/10.3390/ijms22168853

AMA Style

Rossi C, Fernàndez A, Torres P, Ramirez-Nuñez O, Granado-Serrano AB, Fontdevila L, Povedano M, Pamplona R, Ferrer I, Portero-Otin M. Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment. International Journal of Molecular Sciences. 2021; 22(16):8853. https://doi.org/10.3390/ijms22168853

Chicago/Turabian Style

Rossi, Chiara, Anna Fernàndez, Pascual Torres, Omar Ramirez-Nuñez, Ana Belén Granado-Serrano, Laia Fontdevila, Mònica Povedano, Reinald Pamplona, Isidro Ferrer, and Manuel Portero-Otin. 2021. "Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment" International Journal of Molecular Sciences 22, no. 16: 8853. https://doi.org/10.3390/ijms22168853

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